Regulation of OPA1 processing and mitochondrial fusion by m-AAA protease isoenzymes and OMA1.
Regulation of OPA1 processing and mitochondrial fusion by m-AAA protease isoenzymes and OMA1.
复制标题
DOI：
10.1083/jcb.200906084
复制
发表时间：
2009-12-28
期刊：
影响因子：
--
通讯作者：
Langer T
中科院分区：
文献类型：
--
作者：
Ehses S;Raschke I;Mancuso G;Bernacchia A;Geimer S;Tondera D;Martinou JC;Westermann B;Rugarli EI;Langer T
m-AAA蛋白酶切割OPA1以确保长和短的OPA1异构体的平衡，而OMA1的切割导致短的OPA1变体的积累。（另见Head等人在本期发表的论文。）线粒体融合依赖于动力蛋白样鸟苷三磷酸酶OPA1，其活性由蛋白水解裂解控制。线粒体功能障碍诱导OPA1加工并导致线粒体断裂，允许选择性去除受损的线粒体。在这项研究中，我们证明了两类金属肽酶调节线粒体内膜中OPA1的切割：三磷酸腺苷（ATP）依赖基质AAA（与多种细胞活性相关的ATP酶[m-AAA]）蛋白酶的同工酶，保守亚基paraplegin， AFG3L1和-2的可变组合，以及ATP独立的肽酶OMA1。m-AAA蛋白酶的功能冗余同工酶确保线粒体融合所需的OPA1长和短同工酶的平衡积累。小鼠组织中AFG3L2的缺失，小鼠胚胎成纤维细胞中AFG3L1和-2的下调，或人类细胞中AFG3L2显性阴性变体的表达降低了长亚型OPA1的稳定性，并诱导了OMA1对OPA1的加工。此外，如果线粒体DNA被耗尽或线粒体活性受损，OMA1的切割会导致短的OPA1变异体的积累。我们的研究结果将不同的肽酶与构成和诱导的OPA1加工联系起来，并揭示了与m-AAA蛋白酶亚基突变相关的神经退行性疾病的发病机制。
m-AAA proteases cleave OPA1 to ensure a balance of long and short OPA1 isoforms, whereas cleavage by OMA1 causes an accumulation of the short OPA1 variants. (See also companion paper from Head et al. in this issue.) Mitochondrial fusion depends on the dynamin-like guanosine triphosphatase OPA1, whose activity is controlled by proteolytic cleavage. Dysfunction of mitochondria induces OPA1 processing and results in mitochondrial fragmentation, allowing the selective removal of damaged mitochondria. In this study, we demonstrate that two classes of metallopeptidases regulate OPA1 cleavage in the mitochondrial inner membrane: isoenzymes of the adenosine triphosphate (ATP)–dependent matrix AAA (ATPase associated with diverse cellular activities [m-AAA]) protease, variable assemblies of the conserved subunits paraplegin, AFG3L1 and -2, and the ATP-independent peptidase OMA1. Functionally redundant isoenzymes of the m-AAA protease ensure the balanced accumulation of long and short isoforms of OPA1 required for mitochondrial fusion. The loss of AFG3L2 in mouse tissues, down-regulation of AFG3L1 and -2 in mouse embryonic fibroblasts, or the expression of a dominant-negative AFG3L2 variant in human cells decreases the stability of long OPA1 isoforms and induces OPA1 processing by OMA1. Moreover, cleavage by OMA1 causes the accumulation of short OPA1 variants if mitochondrial DNA is depleted or mitochondrial activities are impaired. Our findings link distinct peptidases to constitutive and induced OPA1 processing and shed new light on the pathogenesis of neurodegenerative disorders associated with mutations in m-AAA protease subunits.
登录
查看更多内容
影响因子：
16
作者：
Augustin, Steffen;Gerdes, Florian;Lee, Sukyeong;Tsai, Francis T. F.;Langer, Thomas;Tatsuta, Takashi
通讯作者：
Tatsuta, Takashi
影响因子：
5.3
作者：
Delettre, C;Griffoin, JM;Hamel, CP
通讯作者：
Hamel, CP
DOI：
10.1083/jcb.200403022
发表时间：
2004-04-26
期刊：
The Journal of cell biology
影响因子：
--
作者：
Herlan M;Bornhövd C;Hell K;Neupert W;Reichert AS
通讯作者：
Reichert AS
影响因子：
3.3
作者：
Koppen, Mirko;Bonn, Florian;Langer, Thomas
通讯作者：
Langer, Thomas
影响因子：
4.8
作者：
Olichon, A;Baricault, L;Lenaers, G
通讯作者：
Lenaers, G